The routes leading to programmed cell death are as tightly regulated as those of cellular growth and proliferation, and a finely synchronized balance between the life and death of cells ensures proper organ size and function. Inhibitors of apoptosis (IAPs) proteins were initially characterized by their ability to directly bind and inhibit apoptotic caspases. However, recent studies have clarified that IAPs are much more functionally versatile, modulating a vast range of signaling pathways that have an impact on antimicrobial responses, tumorigenesis, metastasis and cellular migration. A significant contribution of IAPs in tumorigenesis is their inherent function as E3 ubiquitin ligases to modulate cellular signaling downstream of death receptors or certain pattern recognition receptors. In this review, we focus on modulation of the innate and adaptive immune systems, macrophage plasticity and inflammatory responses by IAP family members. We also explore the rationale to target IAPs pharmacologically for the treatment of a number of inflammatory diseases and cancer.